The high prevalence of obesity in the United States suggests a lack of existing medical treatments. Most of the existing anorectic agents carry high risks and provide limited efficacy, precluding them as treatments of choice for the management of moderate overeating. Since there is a growing awareness in the medical community that obesity and its side-effects can require aggressive medical intervention, new anti-obesity agents with improved performance characteristics are inclined to be well received.
Although the classification and biochemical mechanisms of obesity and related eating disorders are not clearly defined, their broadening acceptance as disease states suggests a need to design safe and effective pharmacotherapies. The most commonly used weight control agents available without prescription are adrenergic stimulants such as phenylpropanolamine and phenethylamine derivatives. Although effective appetite inhibitors, adrenergic agents produce numerous untoward side effects, such as nervousness, irritability, insomnia, dizziness, tachycardia, palpitations, hypertension, and the like. These side effects may be severe enough to require cessation of treatment. The actual safety of such adrenergic agents is questionable, particularly since 20-30% of the U.S. population suffer from hypertension. Kopf, DE 3,430,389, disclosed weight reduction by administering a combination of an adrenergic agent with a benzodiazepine sedative. Although the non-stimulant anorectic agent fenfluramine is devoid of the psychomotor stimulant properties and abuse potential seen with stimulant-like compounds (e.g., amphetamine), it often has an inadequate clinical efficacy, and patients receiving the drug often complain of drowsiness and headache. Thus, it is apparent that none of the current anti-obesity pharmaco-therapies available are particularly satisfactory.
Tetrahydro-.beta.-carboline (THBC) has a variety of pharmacological actions and has been variously evaluated as a cholinesterase inhibitor, sedative/hypnotic, analgesic, and psychotomimetic. It competes with low affinity for brain tryptamine, imipramine, 5-hydroxytryptamine (5-HT), and spiperone binding sites, enhances epolarization- induced 5 HT efflux from brain slices, and weakly inhibits 5-HT uptake in brain synaptosomes and 5-HT oxidative deamination. It occurs naturally in mammalian brain tissue.
When THBC is administered parenterally to laboratory animals, it suppresses locomotion, exploratory activity, and conflict behavior, impairs performance on operantly conditioned learning and memory tasks, reduces seizure susceptibility, prolongs barbiturate sedation, and antagonizes specific drug induced stereotypic behavior. When given in high doses, THBC induces a characteristic behavioral syndrome characterized by hyperactivity, forepaw treating, body weaving, and circling. Paradoxically, THBC has been reported to reduce motor activity, induce apparent anxiety, and increase voluntary ethanol consumption when administered intraventricularly to rats. Atkinson, GB 1,183,219 disclosed its use as an analgesic.
Physiological actions of THBC include effects on endocrine secretory patterns and body temperature. Systemic administration in rodents produces a dose-dependent elevation of plasma prolactin levels, decreased serum luteinizing hormone levels, and elevated plasma corticosterone. THBC elicits significant hypothermia when administered to rats parenterally in doses of 6.25 mg/Kg or greater.
It is also known that daily oral administration of THBC produces temporary dose-related decrements in food and fluid intake in rats. Animals that receive average daily amounts of THBC in excess of 49 mg/Kg show significant reductions in food intake after two consecutive days of treatment; however, tolerance develops, and food consumption returns to normal by the twelfth treatment day. Smaller daily doses (less than 30 mg/Kg) do not significantly alter appetite. It is noteworthy that in Rommel-spacher's report, 6 out of the 24 animals receiving 49 mg/Kg/day or greater died.
Payne et al, U.S. Pat. No. 4,336,260 disclosed the use of 1 aryl-3-carboxylic acid THBC derivatives as antidepressants.
S. Cooper disclosed that three fully-unsaturated .beta.-carboline derivatives exhibit hyperphagic activity, while another .beta.-carboline derivative exhibits anorectic activity. The hyperphagic derivatives were: ethyl 6-benzyloxy-4-meth-oxymethyl-.beta.-carboline-3-carboxylate, ethyl-5-benzyloxy-4-methoxymethyl .beta.-carboline-3-carboxylate, and ethyl -isopropoxy-4-methyl-.beta.-carboline-3-carboxylate. The anorectic derivative was .beta.-carboline-3-carboxylic acid methyl amide, which when injected intraperitoneally at 10.0 mg/Kg, reduced food consumption by partially sated rats to 30% of control.
It has been reported (Skolnick) that certain carboxy-ester beta-carboline derivatives bind with high affinity to benzodiazepine receptors. This binding may account for the ability of these compounds to antagonize the anticonvulsant, anxiolytio, and sedative properties of benzodiazepine drugs. However, saturated derivatives such as 3-carbomethoxy-1,2,3,4-tetrahydro-.beta.-carboline bind with very low affinity (Skolnick; Robertson).